Several studies have demonstrated low serum folate concentrations in patients with schizophrenia compared to controls and an association with the common methylenetetrahydrofolate reductase (MTHFR) C677T mutation which results in decreased folate metabolic activity. We have linked negative symptoms and cognitive impairment to low folate serum concentrations and to the MTHFR C677 polymorphism in schizophrenia. In addition, folate 2 mg/d and B12 were recently reported to improve symptoms in 42 schizophrenia patients with elevated homocysteine in a placebo-controlled 12 week trial. This finding is very promising but requires replication and further characterization. We have made several revisions to our study design in response to reviewers' comments, including increasing the sample size to allow for drop-outs, extending the trial to 6 months, and adding B12 to the folate supplementation. Methods: We propose a 24-week, randomized, placebo-controlled, parallel group add-on trial of folate 2 mg/d plus B12 400 micrograms in 144 schizophrenia patients with moderate-or-greater negative symptoms treated with second generation antipsychotics. Our primary endpoint is reduction in negative symptoms. We will also assess cognitive functioning. Potential predictors of response will be assessed, including baseline serum and red blood cell folate concentrations, homocysteine and B12 concentrations, MTHFR C677 polymorphism status and change in folate and B12 concentrations during treatment. Previously-raised ethical concerns about the use of a placebo group will be addressed by excluding patients with elevated plasma homocysteine levels or with megaloblastic anemia, and women who are pregnant. Significance: This study examines two very safe and inexpensive vitamins which serve multiple roles related to brain development and function, including protection against neurotoxicity, synthesis of neurotransmitters and methylation of DNA. Recent findings suggest that folate supplementation may improve negative symptoms and cognitive deficits of schizophrenia-symptoms which confer substantial disability and for which no effective treatments are currently available. This will be the first adequately-powered study to assess efficacy and identify predictors of response. [unreadable] [unreadable] [unreadable]